Field of the Invention
The present invention relates to medicinal substances. More specifically, the invention pertains to a medicament in particle form, with one or more anionic or partially anionic active ingredients, preferably nucleic acids, oligonucleotides, proteins, peptides, or biological macromolecules, which are bound by ionic interactions to a carrier material that has the following structure ##STR1## where N=particulate mixed polymer or homopolymer of acrylic 30 acid or acrylate or methacrylates in a molar ratio of p:n from 0:100 to 99:1; O=oxygen of the ester group; X=branched or unbranched alkyl chain with 2 to 10 carbon atoms; B=--NR.sub.2 where R=H and low alkyl chains in an arbitrary combination; E=H or low alkyl chain, with a particle size distribution of 10 to 1000 nm. The particles on which the invention is based, whose size is on the order of 10 to approximately 1000 nm, have the object of assuring not only the binding of relevant oligomeric or macromolecular structures but also of protecting them against enzymes that degrade them and of transporting substances purposefully to the site of action and through the cell membrane.
The particles on which the invention is based are synthesized or condensed from suitable monomer building blocks by means of polymerization reactions. Suitable monomers are substances that after the polymerization produce a water-insoluble, physiologically compatible product. Acrylates or methacrylates, with or without basic modifications, are preferably used. Acrylates or methacrylates with basic modifications are distinguished in that the alkyl chains have from 2 to 10 carbon atoms. Chain lengths of 4 to 10 and in particular 5 to 8 carbon atoms should preferably be used, because this assures optimal availability of the basic amino groups for binding the applicable substances.
As the polymerization mechanism, a radical or ionic polymerization in an aqueous or organic phase or a corresponding mixture of water and an organic solvent, such as acetone or ethanol, can be chosen. Once the polymerization is ended and the solvent is removed, the carrier substance can be resuspended in water or preferably in physiologically compatible buffer media.
If a monomer with a protected amino group is used for the condensation, preferably a trifluoroacetyl protective group, then this group can be removed by heating with ammonia in the autoclave. Optionally, a suitable cleaning step, preferably dialysis, can follow.
The carrier materials thus produced are particulate in nature and have a particle size of 10 to 1000 nm; a particle size of 50 to 500 nm and in particular 50 to 300 nm is a preferable goal. Moreover, the carrier material, suspended in water, has a positive surface charge, characterized by a positive Zeta potential.
The carrier material according to the invention is preferably used for binding nucleic acids, such as oligonucleotides, or also peptides, on the basis of ionic interactions.
Compared with existing techniques for binding oligonucleotides, such as antisense oligonucleotides, or binding plasmids that are used for gene transfer and are based on binding the active ingredients to liposomal carriers (lipofectin), the invention has the substantial advantage that compared with liposomal preparations, it is a solid, particulate carrier material with substantially higher stability in aqueous suspensions. In contrast to lipofectin, the carrier material of the invention can be prepared in various forms for various kinds of administration. For example, it can be used in compressed form as an implant, which releases the active ingredient in controlled fashion over a certain period of time, or as an oral form of medicament that can be produced by compression.
Compared with previously used particulate carriers, such as nanoparticles on an alkylcyanoacrylate basis, the invention provides for the advantage that specific functional groups can be incorporated into the polymer structure that assure a targeted binding of the active ingredient on the basis of ionic interactions. In the prior art, particulate carriers developed until now, both on an alkylcyanoacrylate basis and a methacrylate basis, exhibit no binding or only inadequate binding. The previously known nanoparticulate forms of medicament, however, do not have the basic functional groups described in the present invention. A binding of active ingredients to previously known nanoparticles, usually methyl methacrylates, takes place nonspecifically by adsorption effects of lipophilic substances to surfaces or by encapsulation or embedding in the polymer structure.
Particles on an acrylate basis in microparticulate form, which have basic modifications, are also known. Those carrier materials are substantially distinguished from the present invention in that they have a particle size of &gt;1 .mu.m. Such preparations are often used as starting products for producing coatings on tablets or for producing deposition matrix systems for oral or transdermal forms of medication (EP 0 164 669 A2, EP A 0 315 219). Parenteral application in the form of an IV application of such microparticulate carrier materials as an independent form of medication has not been known until now.
Although the invention is illustrated and described herein as embodied in a medicament in particulate form, it is nevertheless not intended to be limited to the exemplary details described, since various modifications and structural changes may be made therein without departing from the spirit of the invention and within the scope and range of equivalents of the claims.
The construction and method of operation of the invention, however, together with additional objects and advantages thereof will be best understood from the following description of specific examples, partly with reference to the appended figures of the drawing.